Dialysate solution containing hydroxypropyl-beta-cyclodextrin and method of using same

ABSTRACT

A dialysate solution suitable for peritoneal dialysis and containing hydroxypropyl-beta-cyclodextrin is disclosed.

DESCRIPTION

1. Technical Field

This invention relates to a dialysate suitable for peritoneal dialysisas well as for detoxification by hemodialysis, and method of using same.

2. Background Art

Dialysis is most commonly used in the treatment of patients who sufferfrom kidney loss or kidney malfunction. Dialysis is also effective inthe treatment of drug overdoses.

A widely used method of dialysis is extracorporeal hemodialysis. Herethe patient's blood is cleansed by passing it through an artificialkidney in an artificial kidney dialysis machine. By the process ofdiffusion across a semipermeable membrane in the artificial kidney intoa dialysate, impurities and toxins, including drugs, are removed fromthe patient's blood. Water is also removed from the patient's blood bydiffusion. This process of removing water is called ultrafiltration.

Hemodialysis is generally required three times a week, each sessionrequiring 4 to 5 hours in a dialysis center or at home. During dialysis,the patient is "tied" to the machine by venous and arterial blood lineswhich convey the blood to and from the artificial kidney. The activitieswhich the patient can perform are limited while tied to the machine.Thus, the patient's life is seriously affected as his or her dailyactivities must be planned around these sessions.

Another method of dialysis is peritoneal dialysis. There are two typesof such dialysis, intermittent peritoneal dialysis and continuousambulatory peritoneal dialysis.

With intermittent peritoneal dialysis a dialysate, typically containingglucose as an osmotic agent, is infused into the patient's peritonealcavity by means of tubing and a catheter. The peritoneum, which definesthe peritoneal cavity, is a membrane lining the abdomen and pelvicwalls. It contains many small blood vessels and capillary beds which actas a natural semipermeable membrane. This natural membrane may becontrasted with the artificial membrane used in hemodialysis. In bothcases impurities, toxins, and water in the blood are removed bydiffusion across a membrane, a cellulose membrane of an artificialkidney or a peritoneal membrane of a peritoneal cavity.

The dialysate remains in the patient's peritoneal cavity for a timesufficient for blood waste-products and water to be removed by diffusionacross the peritoneal membrane and into the dialysate. Thewaste-products and water containing dialysate then is drained from theperitoneal cavity by means of a catheter and tubing and a fresh supplyof dialysate is infused. Intermittent peritoneal dialysis (IPD) utilizespumps or other auxilliary equipment to which the patient is "tied"during dialysis. The patient must remain sedentary while "tied" to theequipment. Here also, the patient's activities are seriously impeded.

Continuous ambulatory peritoneal dialysis (CAPD) has the importantadvantage of enabling the patient to be ambulatory and conduct a normalroutine during dialysis. The patient is not "tied" to a machine. Thepatient need be sedentary only for the time required to drain and infusedialysate from and into the peritoneal cavity. This infusion anddraining is handled by tubing connected to a surgically implanted,indwelling catheter in the patient's abdominal wall in communicationwith his peritoneal cavity. The patient fills his peritoneal cavity withdialysate, typically the same glucose-containing dialysate used inintermittent peritoneal dialysis, from a collapsible plastic container.When the container is empty, it is not disconnected from the tubingleading into the patient's peritoneal cavity. Instead, the patientsimply rolls up or folds the container and tucks it into his clothing.When it is time to drain the solution from his peritoneal cavity, heremoves the folded container and drains directly into it. Once full, thepatient then replaces the container with a container of fresh dialysate.

Peritoneal dialysates which use glucose as the osmotic agent haveseveral disadvantages, however. One disadvantage is that high glucoseconcentration in the peritoneal dialysate causes glucose to diffusethrough the peritoneum into the bloodstream, providing unwanted caloricinput to the patient and causing excessive weight gain (obesity) andelevated triglyceride levels in the patient as well. This absorption ofglucose is detrimental to patients with heart disease, lung disease ordiabetes.

Another disadvantage is that the diffusion of glucose into thebloodstream reduces the osmolarity, and hence the efficacy, of theperitoneal dialysate. This results in a phenomenon known as "negativeultrafiltration" whereby excess water is added to the patient instead ofremoved from the patient.

Yet another disadvantage is that the glucose in peritoneal dialysatesmay cause the unwanted loss of amino acids and polypeptides (proteinloss) from the bloodstream of the patient.

In addition the pH of the glucose containing peritoneal dialysate(typically in the acidic pH range 5.2-5.5) is not as physiologic as adialysate having a pH value of 7.4 which some physicians desire. Thisacidic pH range is required for a glucose-containing dialysate toprevent carmelization of the glucose during sterilization of thedialysate.

A peritoneal dialysate containing beta-cyclodextrin has been reported toaccelerate the removal of intravenously administered toxins in rats.However, it was found that high concentrations of beta-cyclodextrin weretoxic. See Perrin et al. "Beta-Cyclodextrin As An Aid To PeritonealDialysis. Renal Toxicity Of Beta-Cyclodextrin In The Rat," ResearchCommunications in Chemical Pathology and Pharmacology 19 (2): 373-376(Feb. 1978). Similarly, nephrotoxicity has been reported for methylatedcyclodextrins. See Serfozo et al., "Renal Effects of ParenterallyAdministered Methylated Cyclodextrins on Rabbits," I. Int. Symposium onCyclodextrins, Budapest 1981, pp. 123-132.

The present invention, on the other hand, utilizes a differentcyclodextrin and provides a dialysate which avoids, or at leastminimizes, the aforementioned shortcomings of the prior art.

SUMMARY OF THE INVENTION

The present invention contemplates a glucose-free dialysate. Thisdialysate utilizes hydroxypropyl-beta-cyclodextrin as the osmotic agenttogether with the usual physiologically desirable electrolytes. Tests inlaboratory animals have shown that the present dialysate performscomparably to a dialysate containing glucose as regards to volumebalance and the removal of urea, creatinine, potassium, phosphate andmagnesium. A major advantage of the present dialysate is that a negativeglucose balance can be achieved during dialysis. This result isbeneficial to diabetic patients who require dialysis, patients who areobese, and patients who have high triglyceride and cholesterol levels.

The present invention is also useful in the treatment of drug overdosesby peritoneal as well as hemodialysis inasmuch as a great variety ofdrugs complex with hydroxypropyl-beta-cyclodextrin and are removed fromthe bloodstream during dialysis.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

While this invention is susceptible to embodiment in many differentforms, preferred embodiments of the invention are shown. It should beunderstood, however, that the present disclosure is to be considered asan exemplification of the principles of this invention and is notintended to limit the invention to the embodiments illustrated.

Hydroxypropyl-beta-cyclodextrins are commercially available compoundsthat are derived from beta-cyclodextrins by condensation with apropylene oxide to provide the corresponding hydroxypropyl derivativeshaving a degree of substitution (D.S.) up to about 15 or higher. For thepurposes of the present invention a D.S. value of about 5 to about 7 ispreferred.

The preparation of suitable hydroxypropyl-beta-cyclodextrins isdescribed, inter alia, in International Journal of Pharmaceutics 29(1986):73-82 and in Journal of Pharmaceutical Sciences 75(6):571-572(1986). Also known, and contemplated for the purposes of the presentinvention are the hydroxypropyl-beta-cyclodextrins that are polyethersof cyclodextrins and are obtained by condensation of an excess ofhydroxypropylene oxide with beta-cyclodextrin as described in U.S. Pat.No. 3,459,731 to Gzamera et al.

In accordance with this invention, a peritoneal dialysate is providedcontaining an ion concentration sufficient to cause diffusion of waterand toxins across the peritoneum after infusion of the dialysate intothe peritoneal cavity of a patient. In addition to ahydroxypropyl-beta-cyclodextrin, the present peritoneal dialysatecontains amounts of various physiologically important electrolytes inconcentrations comparable to those in normal plasma water. A suitableperitoneal dialysate of the present invention is represented by thefollowing formulation:

hydroxypropyl-beta-cyclodextrin in an amount of about 5 to about 35g/dl, preferably about 7.5 to about 25 g/dl;

sodium in an amount of about 110 to about 150 mEq/l;

potassium in an amount of about 0 to about 5 mEq/l;

calcium in an amount of about 0 to about 6 mEq/l;

magnesium in an amount of about 0 to about 4 mEq/l; and

alkali equivalent in an amount of about 35 to about 40 mEq/l.

The above constituents and concentrations are merely exemplary, and maybe varied in accordance with patient requirements.

Typical dialysate solution compositions are given in Table I. Theconcentration of each ingredient may vary depending upon the patients'needs, kidney function, and clinical conditions.

                  TABLE I                                                         ______________________________________                                        Typical Dialysate Solution Compositions                                                   Formulation                                                                              Formulation                                                                              Formulation                                 Ingredient  1          2          3                                           ______________________________________                                        HPBCD (% W/V)                                                                             7.5        15         25                                          Sodium (mEq/l)                                                                            135        130        120                                         Potassium (mEq/l)                                                                         3          2.5        2                                           Calcium (mEq/l)                                                                           4          3.5        3                                           Magnesium (mEq/l)                                                                         1.5        1          1                                           Anions.sup.1                                                                              Q.S.       Q.S.       Q.S.                                        pH adjust to                                                                              7.4        7.4        7.4                                         ______________________________________                                         .sup.1 As lactate, acetate or chloride. The presence of these anions is       essential to maintain the acidbase balance of the body. Also, they            contribute to achieving the desired osmotic pressure and electrolyte          balance.                                                                 

The present dialysate can be compounded by the following procedure(Formulation 1 per liter):

1. Weigh the exact amount of pyrogen-freehydroxypropyl-beta-cyclodextrin (HPBCD) (75 grams), and dissolve inapproximately 700 milliliters of deionized water for injection.

2. Weigh the exact amount of sodium (135 milliequivalent), potassium (3milliequivalent), calcium (4 milliequivalent) and magnesium (1.5milliequivalent) salts, and add to the solution prepared in step #1.

3. Adjust the pH to 7.4 by the addition of 1 normal HCl or 1 normalNaOH. Also, measure and adjust, if needed, the osmolality using anosmometer. Adjust the final volume to one liter by adding deionizedwater for injection.

4. The final solution is then sterilized by filtration, using about a0.22 micron filter, or other appropriate sterilization methods.

5. In a sterile environment, the solution is then put into sterilecontainers.

6. Microbiol and sterility tests are then performed according to UnitedStates Pharmacopeia (U.S.P.) procedures.

7. Particulate matters are then analyzed according to U.S.P.requirements.

The present dialysate is utilized by introducing an aliquot of thedialysate into the peritoneal cavity of a patient in need of dialysis,maintaining the introduced dialysate in the peritoneal cavity for a timeperiod sufficient for toxins to enter the dialysate, usually for a timeperiod of about 2 to about 8 hours, and thereafter removing from theperitoneal cavity a dialysate aliquot having an increased toxin content.

A study was conducted to compare glucose andhydroxypropyl-beta-cyclodextrin (HPBCD) as osmotic agents in peritonealdialysates.

The two solutions used in this study were: (1) a commercial, standardperitoneal dialysis solution (SPDS) containing 1.5 wt.-% glucose andhaving a pH of about 5.2 to 5.4, (Dianeal® Peritoneal Dialysis Solution,Baxter Laboratories) as reference, and (2) an equi-osmolar solution ofHPBCD (7.5% W/V) that was substantially the same as the commercial 1.5wt.-% glucose solution except for HPBCD replacing glucose.

The composition of Dianeal® is as follows (per liter): sodium chloride,567.0 mg; calcium chloride, 22.1 mg; magnesium chloride, 15.2 mg; sodiumacetate, 392.0 mg; and glucose, 15,000 mg. The osmolality is 347milliosmoles per kilogram (mOsm/kg), and the pH is 5.2 to 5.4.

The study involved evaluation of HPBCD instilled intraperitoneally as aneffective agent for removal of uremic toxins. The elements of the studyinvolved:

a. Solutions: Two different solutions were utilized:

1. SPDS containing 1.5 weight percent glucose.

2. SPDS where the glucose is replaced by 7.5 weight percent HPBCD.

Solution 2 shows that HPBCD can replace glucose as an osmotic agent inperitoneal dialysis.

b. Animal model: Uremia was induced in adult rats weighing 350 to 400grams by complete right nephrectomy and partial cryoinfarction of 60 to80% of the left kidney. The uremia was induced by a two step surgicalprocedure under anesthesia. The peritoneal dialysis was done one weekafter the induction of uremia to allow for the development of fulluremic toxicity and accumulation of waste products. It is usual for ratsprepared in this fashion to have blood urea nitrogen (BUN) levels ofbetween 120 to 140 mg/dl. Rats with this BUN level will survive forseveral weeks, long enough to perform the intended acute studies. Tenrats were allocated to each group, but 25 rats were prepared to allowfor possible loss due to experimental accidents or unexpecteddevelopments.

c. Dialysis procedure: Rats were anesthetized by inactin, a long actingbarbiturate, and placed on heating pads to maintain body temperature atnormal levels. A tracheostomy was performed and one carotid artery wascannulated with a PE 50 catheter to allow blood sampling. A PE 90catheter was introduced percutaneously into the peritoneal cavitythrough an 18 gauge needle inserted in the midline of the abdomen. Theneedle was removed and the catheter connected to a syringe containingthe dialysate solution. Half an hour after the end of surgery, 2 ml ofblood were withdrawn through the carotid catheter, the plasma separatedby centrifugation and the red blood cells (RBC) reinfused. The plasmawas used to measure predialysis BUN, creatinine, Na, K, osmolarity andphosphate. After reinfusion of the RBC, dialysate warmed to 37° C. wasinstilled in the abdominal cavity via the PE 90 catheter at a volume of10 ml/100 grams body weight. The dwell time was two hours. One hourafter instillation of the peritoneal dialysate, 2 ml of blood werewithdrawn through the carotid catheter, the plasma separated bycentrifugation and the RBC reinfused. At the end of the dwell time, thedialysate was removed, its volume measured and the solution saved forperformance of the following measurements: BUN, creatinine, Na, K,osmolarity, phosphate and total protein. After the dialysate wasremoved, a blood sample was obtained through the carotid catheter forthe same measurements done on predialysis and middle dialysis plasmasamples.

d. Calculations: The measurements performed allowed calculation ofclearance of small molecules such as BUN, middle molecule such ascreatinine, and changes in electrolytes, and protein loss into theperitoneal fluid. These measurements also allowed evaluation of theultrafiltration rate and the fluid removal.

The results are set forth in Table II, below.

                  TABLE II                                                        ______________________________________                                        Results of Comparative Dialysis                                               (mean ± st.dev ,n = 5)                                                                      Dialysate                                                                     Glucose HPBCD                                                ______________________________________                                        Volume in                                                                     Absolute (ml)      43.8 ± 8.6                                                                           40.6 ± 7.5                                    Per body weight (ml/100 g)                                                                       14.2 ± 1.4                                                                           14.6 ± 0-2                                    Volume out                                                                    Absolute (ml)      39.4 ± 3.5                                                                           39.4 ± 2.4                                    Per body weight (ml/100 g)                                                                       13.2 ± 1.5                                                                           13.9 ± 0.4                                    Urea removal                                                                  Pre-BUN.sup.1 (mg/dl)                                                                            144 ± 9                                                                              134 ± 11                                      Post-BUN (mg/dl)   124 ± 13                                                                             125 ± 16                                      Urea removed                                                                  Absolute (mg)      46 ± 12                                                                              42 ± 5                                        Per ml (mg/ml)     1.1 ± 0.2                                                                            1.1 ± 0.1                                     Creatinine removal                                                            Pre-creatinine (mg/dl)                                                                           3.9 ± 0.1                                                                            3.9 ± 0-4                                     Post-creatinine (mg/dl)                                                                          3.3 ± 0.7                                                                            3.3 ± 0.4                                     Creatinine removed                                                            Absolute (mg)      1.1 ± 0.3                                                                            0.99 ± 0.1                                    Per ml (g)         27.4 ± 4.6                                                                           25.2 ± 3.6                                    Removal of other compounds                                                    Potassium (Eq)     154 ± 71                                                                             183 ± 43                                      Phosphate (mg)     2.7 ± 1.1                                                                            2.6 ± 0.3                                     Magnesium (g)      166 ± 158                                                                            180 ± 107                                     Uric acid (mg/dl) range                                                                          0.2 to 0.4                                                                              0.2 to 0.7                                       Glucose balance    (negative values reflect                                                      removal of glucose                                                            from animal)                                               Glucose in dialysate (mg/dl)                                                  Pre-dialysis       1500      0                                                Post-dialysis      548 ± 162                                                                            114 ± 28                                      Glucose balance (mg)                                                                             428 ± 94                                                                             -45 ± 11                                      ______________________________________                                         .sup.1 Blood urea nitrogen                                               

As can be seen, the performance of the glucose dialysate is comparableto the HPBCD dialysate in the removal of undesirable constituents.However, the clear superiority of the HPBCD dialysate over the glucosedialysate can be readily appreciated when the glucose balance isanalyzed. The HPBCD dialysate actually reduces the level of glucose inthe bloodstream! In contradistinction, the glucose dialysate increasesthe glucose in the bloodstream which, as previously mentioned, isdetrimental as this provides unwanted glucose calories, adverselyaffects patients with heart disease, lung disease, obesity or diabetes.Also, diffusion of glucose to the bloodstream reduces the osmolarity,and hence the efficacity, of the dialysate necessitating more volume ofdialysate per day. While uric acid results are not conclusive, thehigher uric acid concentration in HPBCD dialysate suggests higherremoval capacity for this solution than for glucose.

Reports in literature, including the previously mentioned Perrin, et al.report, have shown beta-cyclodextrin (BCD) to be toxic to laboratoryanimals. The use of BCD results in an enlargement of the kidneys anddeath due to kidney failure (i.e., BCD is nephrotoxic).

A first study was conducted to determine the relative nephrotoxicity ofHPBCD and BCD. A control group using phosphate buffer solution was alsoincluded in the study.

Three groups of normal rats were utilized in this study. The solutions,which were administered intraperitoneally, all had a pH of 7.4, atemperature of 37° C. and were instilled at a dosage of 15 ml/100 g bodyweight. Group I rats were given the vehicle solution of phosphate buffersaline (PBS). Group II rats were subdivided into three sub-groups. Thefirst sub-group received a solution having a concentration of 1.5%HPBCD, the second sub-group received a solution having a concentrationof 3% HPBCD while the third sub-group received a solution having aconcentration of 6% HPBCD. Group III rats were given a solution having aconcentration of 0.75% BCD.

Animals from each group were sacrificed at 24 and 72 hours afterinjection of the peritoneal solution. The animals were sacrificed undergeneral anesthesia and exsanguinated from the abdominal aorta. Plasmawas separated and blood urea nitrogen and creatinine was measured andused as an index of renal toxicity of the solutions.

The results of the study are presented in TABLES III, and IV below:

                  TABLE III                                                       ______________________________________                                        Summary of Nephrotoxicity Results                                                    Control                                                                       Group                                                                         Phoshate                                                               Para-  Buffer    BCD Group.sup.1                                                                             HPBCD Group                                    meter  1 and 3 day                                                                             1 day    3 day  1 day.sup.2                                                                          3 day.sup.3                           ______________________________________                                        Mortality                                                                            0/6       1/6      8/9    0/6    0/6                                   (died/                                                                        total)                                                                        Kidney normal    enlarged enlarged                                                                             normal normal                                size                                                                          Kidney normal    increased                                                                              increased                                                                            normal normal                                weight                                                                        BUN    15.5.sup.4                                                                              79.4     animals                                                                              14.8   19.8                                  (mg/dl)                   died                                                Con-   no kidney kidney   kidney no     no                                    clusion                                                                              damage    failure  failure                                                                              kidney kidney                                                                 damage damage                                ______________________________________                                         .sup.1 0.75% w/v solution. 15 ml/100 g body weight.                           .sup.2 Both 1.5 and 3% w/v solutions were used for the 1 day group. 15        ml/100 g body weight.                                                         .sup.3 Both 1.5 and 3% w/v solutions were used for the 3 day group. 15        ml/100 g body weight.                                                         .sup.4 Normal BUN                                                        

                                      TABLE IV                                    __________________________________________________________________________    Summary of Nephrotoxicity Results                                                     Wt (i)                                                                            Wt (f)                                                                            Rt kd                                                                             Rt kd/wt                                                                           Lt kd                                                                             Lt kd/wt                                                                           BUN Mortality                               GROUP   g   g   mg  mg/g mg  mg/g mg/dL                                                                             %                                       __________________________________________________________________________    CONTROL 1d                                                                            216                                                                              213  809 3.78 813 3.8  15.5                                                                              0                                       (n = 6) 15.4*                                                                            13   0   0.14 70  0.16 3.8                                         HPBCD 1d                                                                              213                                                                              210  860 4.08 867 4.11 14.8                                                                              0                                       (n = 6) 1.5%                                                                          17.3*                                                                            15.8 86  0.29 84  0.22 2.9                                         HPBCD 1d                                                                              322                                                                              301  1054                                                                              3.49 1034                                                                              3.43 15.7                                                                              0                                       (n = 6) 3%                                                                            19.6*                                                                            16.1 50  0.12 48  0.19 2.2                                         HPBCD 1d                                                                              240                                                                              227  1066                                                                              4.70 1076                                                                              4.73 14.5                                                                              0                                       (n = 6) 6%                                                                            4.47*                                                                            7.4  59  0.14 114 0.4  3.48                                        BCD 1d  223                                                                              218  1307                                                                              5.98 1272                                                                              5.83 79.4                                                                              16.67                                   (n = 6) 0.75%                                                                         10.2*                                                                            9.1  152 0.82 153 0.88 22.7                                        CONTROL 3d                                                                            271                                                                              259  991 3.84 960 3.71 17.7                                                                              0                                       (n = 7) 41.3*                                                                            40.5 138 0.3  146 0.32 3.8                                         HPBCD 3d                                                                              296                                                                              280  1009                                                                              3.61 1027                                                                              3.68 19.8                                                                              0                                       (n = 6) 1.5%                                                                          34.1*                                                                            27.5 90  0.26 74  0.32 2.7                                         HPBCD 3d                                                                              275                                                                              267  1009                                                                              3.78 995 3.72 19.9                                                                              0                                       (n = 6) 3%                                                                            26*                                                                              22.7 89  0.25 88  0.19 3.77                                        BCD 3d  -- --   --  --   --  --   --  77.78                                   (n = 9) 0.75%                                                                 __________________________________________________________________________     Wt (i) = initial body weight                                                  Wt (f) = final body weight, i.e., at time of sacrifice                        Rt kd = Right kidney                                                          Lt kd = Left kidney                                                           wt = Body weight                                                              BUN = Blood Urea Nitrogen                                                     Control = Phosphate buffer solution                                           HPBCD = Hydroxypropylbeta-cyclodextrin; D.S. = about 5                        1d = 1 day                                                                    3d = 3 day                                                                    n = Number of animals                                                         * = Standard deviation                                                        BCD = Betacyclodextrin                                                   

One rat in the BCD 1d Group and all but two of the nine rats in the BCD3rd Group died of kidney failure. None of the rats in the HPBCD orControl Groups died, notwithstanding the fact that the concentration ofHPBCD in the HPBCD solutions was two, four or eight times that of theconcentration of BCD in the BCD solutions.

As part of the toxicological evaluation of HPBCD, control groups ofanimals were dosed with HPBCD alone. The results of the studies relatingto HPBCD and a saline control are described below.

(a) Studies in rats

Two groups (5/sex/group) of rats [Crl:CD(SD) BR strain] were used forthis study. Control rats were given 200 mg of salt per kilogram of bodyweight intravenously administered in a saline control solutioncomprising 20% salt by weight in water. The saline control wasadministered every second day for 14 days (i.e. seven injections). Thetreated rats were given 200 mg of HPBCD per kilogram of body weightintravenously administered (200 mg/kg i.v. HPBCD) via a HPBCD solutioncontaining 20% HPBCD by weight in water on the same injection schedule.Animals were observed for signs of toxicity. At the end of the study theanimals were necropsied, gross pathology was observed, histopathologicalsamples were prepared and blood was drawn for clinical laboratorymeasurements.

                  TABLE V                                                         ______________________________________                                        Antemortem Observations For Rats Treated                                      Intravenously Every Second Day For 14 Days                                    With Saline Control or HPBCD Solution.                                        Group       Number of deaths                                                                           Number of observations                               ______________________________________                                        Male-saline control                                                                       0/5          0/5                                                  Male-HPBCD  0/5          1/5, bloody crust.sup.1                              Female-saline                                                                             0/5          0/5                                                  control                                                                       Female-HPBCD                                                                              0/5          0/5                                                  ______________________________________                                         .sup.1 Unrelated to treatment.                                           

                  TABLE VI                                                        ______________________________________                                        Body Weight Gain (In Grams) For Rats Treated                                  Intravenously Every Second Day For 14 Days                                    With Saline Control or HPBCD Solution.                                                Saline Control                                                                              HPBCD                                                   ______________________________________                                        Male      week 1 36.8 ± 5.28                                                                         week 1 45.7 ± 4.69                                         week 2 36.6 ± 5.00                                                                         week 2 41.7 ± 5.20                               Female    week 1 16.8 ± 6.55                                                                         week 1 16.0 ± 5.00                                         week 2 19.9 ± 4.38                                                                         week 2 18.0 ± 4.21                               ______________________________________                                    

No difference in body weight gains between the saline control and HPBCDsolution treated groups was observed.

                  TABLE VII                                                       ______________________________________                                        Food Intake (In Grams) For Rats Treated                                       Saline Intravenously Every Second Day For 14                                  Days With Saline Control or HPBCD Solution.                                   Saline Control      HPBCD                                                     ______________________________________                                        Male   week 1  152.3 ± 8.06                                                                            week 1                                                                              144.8 ± 7.77                                    week 2  151.5 ± 10.78                                                                           week 2                                                                              151.1 ± 5 22                             Female week 1   97.8 ± 12.50                                                                           week 1                                                                              107.9 ± 10.59                                   week 2  106.4 ± 9.51                                                                            week 2                                                                              112.1 ± 12.47                            ______________________________________                                    

No difference in food intake between the saline control and HPBCDsolution treated groups was observed.

                  TABLE VIII                                                      ______________________________________                                        Hematology Results For Pre-Study Control                                      Male Rats And Those Given a Saline Control                                    or HPBCD Solution Intravenously Every 2 Days                                  For 14 Days.                                                                             Pre-study                                                          Blood component                                                                          control     Saline control                                                                           HPBCD                                       ______________________________________                                        Red blocd ce11                                                                           6.48 ± 0.27                                                                            8.02 ± 0.19                                                                           7.55 ± 0.17                              (× 10.sup.6 /mm.sup.3)                                                  Hemoglobin 13.1 ± 0.59                                                                            15.6 ± 0.41                                                                           14.6 ± 0.51                              (G/DL)                                                                        Hematocrit (%)                                                                           44.8 ± 1.86                                                                            50.9 ± 0.73                                                                           48.6 ± 1.74                              Mean corpuscle                                                                           69.0 ± 1.10                                                                            63.0 ± 1.10                                                                           64.0 ± 2.20                              (FL)                                                                          Mean corpuscle                                                                           20.2 ± 0.67                                                                            19.5 ± 0.09                                                                           19.3 ± 0.60                              hemoglobin (pg)                                                               Mean corpuscle                                                                           29.2 ± 0.87                                                                            30.6 ± 0.51                                                                           30.0 ± 0.35                              hemoglobin                                                                    concentrative (%)                                                             Platelet count                                                                           1111.8 ± 133.6                                                                         949.0 ± 55.9                                                                          1020.0 ± 79.5                            (× 10.sup.3 /mm.sup.3)                                                  Normal blood                                                                               0 ± 0.3                                                                                0 ± 0.4                                                                               0 ± 0.0                                cells (/100 white                                                             blood cells)                                                                  White blood cells                                                                         7.5 ± 1.79                                                                             8.7 ± 2.23                                                                            7.9 ± 1.18                              (× 10.sup.3 /mm.sup.3)                                                  Segmented  0.65 ± 0.48                                                                            0.67 ± 0.29                                                                           0.61 ± 0.44                              neutrophils                                                                   (× 10.sup.3 /mm.sup.3)                                                  Lymphocytes                                                                              6.64 ± 1.43                                                                            7.85 ± 2.08                                                                           7.13 ± 1.08                              (× 10.sup.3 /mm.sup.3)                                                  Monocytes  0.16 ± 0.13                                                                            0.12 ± 0.23                                                                           0.08 ± 0.01                              (× 10.sup.3 /mm.sup.3)                                                  Eosinophils                                                                              0.01 ± 0.00                                                                            0.02 ± 0.05                                                                           0.07 ± 0.05                              (× 10.sup.3 /mm.sup.3)                                                  Basophils  0.00 ± 0.00                                                                            0.00 ± 0.00                                                                           0.00 ± 0.00                              (× 10.sup.3 /mm.sup.3)                                                  ______________________________________                                    

                  TABLE IX                                                        ______________________________________                                        Hematology Results Fcr Pre-Study Control                                      Female Rats And Those Given a Saline Control                                  or HPBCD Solution Intravenously Every 2 Days                                  For 14 Days.                                                                  Blood     Pre-study                                                           component control    Saline control                                                                            HPBCD                                        ______________________________________                                        Red blood cell                                                                          6.75 ± 0.19                                                                           7.67 ± 0.41                                                                            7.32 ± 1.00                               (× 10.sup.6 /mm.sup.3)                                                  Hemoglobin                                                                              13.2 ± 0.46                                                                           14.8 ± 0.80                                                                            13.6 ± 3.06                               (G/DL)                                                                        Hematocrit (%)                                                                          46.1 ± 1.39                                                                           49.2 ± 2.63                                                                            47.2 ± 5.59                               Mean corpuscle                                                                          68.0 ± 1.30                                                                           64.0 ± 1.50                                                                            65.0 ± 2.70                               (FL)                                                                          Mean corpuscle                                                                          19.6 ± 0.56                                                                           19.3 ± 0.50                                                                            18.4 ± 2.41                               hemoglobin (pg)                                                               Mean corpuscle                                                                          28.7 ± 0.25                                                                           30.0 ± 0.33                                                                            28.6 ± 3.75                               hemoglobin                                                                    concentrative                                                                 (%)                                                                           Platelet count                                                                           1142 ± 99.60                                                                           1105 ± 114.60                                                                          924 ± 395.20                            (× 10.sup.3 /mm.sup.3)                                                  Normal blood                                                                             0.0 ± 0.40                                                                            0.0 ± 0.00                                                                             0.0 ± 0.00                               cells (/100                                                                   white blood                                                                   cells)                                                                        White blood cells                                                                         6.0 ± 1.78                                                                           5.1 ± 0.82                                                                             7.4 ± 2.56                               (× 10.sup.3 /mm.sup.3)                                                  Segmented 0.42 ± 0.20                                                                           0.80 ± 0.28                                                                            0.49 ± 0.22                               neutophils                                                                    (× 10.sup.3 /mm.sup.3)                                                  Lymphocytes                                                                             5.54 ± 1.76                                                                           4.23 ± 0.68                                                                            6.80 ± 2.42                               (× 10.sup.3 /mm.sup.3)                                                  Monocytes 0.02 ± 0.03                                                                           0.05 ± 0.04                                                                            0.05 ± 0.08                               (×10.sup.3 /mm.sup.3)                                                   Eosinophils                                                                             0.00 ± 0.02                                                                           0.03 ± 0.03                                                                            0.06 ± 0.04                               (× 10.sup.3 /mm.sup.3)                                                  Basophils 0.00 ± 0.00                                                                           0.00 ± 0.00                                                                            0.00 ± 0.00                               (× 10.sup.3 /mm.sup.3)                                                  ______________________________________                                    

                  TABLE X                                                         ______________________________________                                        Blood Chemistry Values For Pre-Study Control                                  Male Rats And Those Given a Saline Control                                    or HPBCD Solution Intravenously Every 2 Days                                  For 14 Days.                                                                              Pre-study                                                         Blood component                                                                           control    Saline control                                                                           HPBCD                                       ______________________________________                                        Glucose (mg/dL)                                                                           76.6 ± 11.1                                                                           107.5 ± 16.91                                                                         94.1 ± 7.43                              Total proteins                                                                             5.7 ± 0.18                                                                            6.3 ± 0.34                                                                            6.3 ± 0.18                              (G/dL)                                                                        Albumin (G/dL)                                                                             3.1 ± 0.12                                                                            3.0 ± 0.12                                                                            3.0 ± 0.08                              Globulin (G/dL)                                                                            2.6 ± 0.15                                                                            3.3 ± 0.26                                                                            3.3 ± 0.20                              Abumin/Globulin                                                                           1.2 ± 0.07                                                                             0.9 ± 0.04                                                                            0.9 ± 0.08                              (Ratio)                                                                       Total bilirubin                                                                            0.3 ± 0.06                                                                            0.3 ± 0.07                                                                            0.2 ± 0.04                              (mg/dL)                                                                       Cholesterol 75.0 ± 9.00                                                                            36.0 ± 15.60                                                                         33.0 ± 7.10                              (mg/dL)                                                                       Triglycerides                                                                             106.0 ± 46.20                                                                          56.0 ± 34.00                                                                          57.0 ± 17.10                            (mg/dL)                                                                       Aspartate amino                                                                           108.0 ± 11.80                                                                         109.0 ± 32.50                                                                         124.0 ± 37.36                            transferase                                                                   (IU/L)                                                                        Alanine amino                                                                             29.0 ± 3.10                                                                           22.0 ± 4.10                                                                           24.0 ± 6.70                              transferase                                                                   (IU/L)                                                                        Alkaline    218.0 ± 51.60                                                                         127.0 ± 15.00                                                                         137.0 ± 26.20                            phosphatase                                                                   (IU/L)                                                                        Blood urea  11.2 ± 2.97                                                                           11.2 ± 1.10                                                                           11.2 ± 0.87                              nitrogen (mg/dL)                                                              Creatinine (mg/dL)                                                                         0.8 ± 0.07                                                                            0.8 ± 0.04                                                                            0.8 ± 0.04                              Calcium (mg/dL)                                                                            9.1 ± 0.81                                                                           10.0 ± 0.38                                                                            9.8 ± 0.31                              Ionic phosphate                                                                           10.9 ± 0.60                                                                            9.4 ± 0.72                                                                            9.7 ± 0.34                              (mg/dL)                                                                       Sodium (mmol/dL)                                                                          139.0 ± 1.00                                                                          142.0 ± 1.20                                                                          142.0 ± 1.50                             Potassium (mmol/L)                                                                         4.7 ± 0.42                                                                            4.4 ± 0.25                                                                            4.7 ± 0.15                              Chlorine (mmol/L)                                                                         106.0 ± 1.30                                                                          105.0 ± 3.80                                                                          106.0 ± 1.80                             ______________________________________                                    

                  TABLE XI                                                        ______________________________________                                        Blood Chemistry Values For pre-Study Control                                  Female Rats And Those Given Saline Contol or                                  HPBCD Solution Intravenously Every 2 Days                                     For 14 Days.                                                                             Pre-study                                                          Blood component                                                                          control    Saline control                                                                           HPBCD                                        ______________________________________                                        Glucose (mg/dL)                                                                          86.0 ± 9.35                                                                           102.9 ± 11.52                                                                         100.0 ± 14.07                             Total proteins                                                                            5.7 ± 0.25                                                                            6.5 ± 0.05                                                                            6.5 ± 0.38                               (G/dL)                                                                        Albumin (G/dL)                                                                            3.3 ± 0.12                                                                            3.2 ± 0.11                                                                            3.1 ± 0.08                               Globulin (G/dL)                                                                           2.5 ± 0.17                                                                            3.3 ± 0.11                                                                            3.4 ± 0.26                               Albumin/Globulin                                                                          1.4 ± 0.08                                                                            1.0 ± 0.08                                                                            0.9 ± 0.06                               (Ratio)                                                                       Total bilirubin                                                                           0.3 ± 0.06                                                                            0.3 ± 0.05                                                                            0.3 ± 0.05                               (mg/dL)                                                                       Cholesterol                                                                              74.0 ± 9.00                                                                            48.0 ± 11.70                                                                          52.0 ± 18.60                             (mg/dL)                                                                       Triglycerides                                                                             78.0 ± 22.90                                                                          41.0 ± 11.40                                                                          35.0 ± 12.00                             (mg/dL)                                                                       Aspartate amino                                                                          115.0 ± 25.50                                                                         102.0 ± 24.30                                                                          102.0 ± 162.00                           transferase                                                                   (IU/L)                                                                        Alanine amino                                                                            24.0 ± 3.20                                                                           19.0 ± 2.70                                                                           21.0 ± 2.30                               transferase                                                                   (IU/L)                                                                        Alkaline   169.0 ± 51.00                                                                         100.0 ± 18.40                                                                         109.0 ± 16.20                             phosphatase                                                                   (IU/L)                                                                        Blood urea 11.7 ± 2.43                                                                           11.5 ± 0.43                                                                           13.2 ± 2.52                               nitrogen (mg/dL)                                                              Creatinine  0.6 ± 0.08                                                                            0.8 ± 0.08                                                                            0.8 ± 0.11                               (mg/dL)                                                                       Calcium (mg/dL)                                                                           9.2 ± 0.81                                                                            9.9 ± 0.29                                                                           10.1 ± 0.82                               Ionic phosphate                                                                          105.0 ± 0.49                                                                           8.3 ± 0.88                                                                            8.3 ± 0.82                               (mg/dL)                                                                       Sodium (mmol/L)                                                                          142.0 ± 1.80                                                                          142.0 ± 0.80                                                                          141.0 ± 1.10                              Potassium   4.8 ± 0.54                                                                            4.5 ± 0.38                                                                            4.5 ± 0.16                               (mmol/L)                                                                      Chlorine   111.0 ± 3.00                                                                          108.0 ± 1.50                                                                          107.0 ± 2.60                              ______________________________________                                    

There were no observed clinically significant differences in clinicallaboratory values between a pre-study control group, the saline controlgroup and the HPBCD treated group (TABLES VIII to XI).

                  TABLE XII                                                       ______________________________________                                        Organ Weight to Total Body Weight Ratios                                      Expressed as Weight Percent of Total Body                                     Weight.                                                                       Males               Females                                                   Organ  Saline Control                                                                            HPBCD    Saline Control                                                                          HPBCD                                   ______________________________________                                        Brain  0.7231      0.7153   1.0628    1.0589                                  Heart  0.3656      0.3787   0.4094    0.4079                                  Liver  3.0370      3.0391   3.3634    3.5723                                  Kidney 0.8923      0.9022   0.8810    0.9937                                  Adrenals                                                                             0.0200      0.0212   0.0367    0.0328                                  Salivary                                                                             0.2311      0.2301   0.2546    0.2701                                  glands                                                                        Spleen 0.2000      0.1943   0.1885    0.2246                                  Thymus 0.2555      0.2089   0.2886    0.2904                                  Thyroid                                                                              0.0071      0.0078   0.0083    0.0058                                  Testes 1.0423      1.0209   --        --                                      Prostate                                                                             0.2085      0.2091   --        --                                      Epidi- 0.2658      0.2635   --        --                                      dymes                                                                         Ovaries                                                                              --          --       0.0611    0.0574                                  Uterus --          --       0.2574    0.3278                                  Pituitary                                                                            0.0046      0.0048   0.0064    0.0066                                  ______________________________________                                    

No changes in gross pathology attributable to HPBCD treatment wereobserved and organ to body ratios were not different between the groups(TABLE XII).

It is concluded that a regimen of 200 mg/kg i.v. of HPBCD administeredevery 2 days for 14 days to rats is without toxicological effects.

(b) Studies in monkeys

Two groups (1/sex/group) of Cynomolgus monkeys were used for this study.Control monkeys were given 200 mg of salt per kilogram of body weightintravenously administered as a saline control solution of 20% by weightin water. The saline control was administered every second day for 14days (i.e. 7 doses). The treated monkeys were given 200 mg/kg i.v. HPBCDon the same injection schedule. Animals were observed for signs oftoxicity. At the end of the study the animals were necropsied, grosspathology was observed, histopathology samples were prepared and bloodwas drawn for clinical laboratory measurements.

                  TABLE XIII                                                      ______________________________________                                        Individual Body Weight Data, in Kilograms                                                           Study Week                                              Group           Initiation  1      2                                          ______________________________________                                        Males                                                                         Group 1 - saline control                                                                      3.14        3.15   3.17                                       Group 2 - HPBCD 2.86        2.81   2.88                                       Females                                                                       Group 1 - saline control                                                                      2.77        2.80   2.78                                       Group 2 - HPBCD 2.73        2.74   2.74                                       ______________________________________                                    

                  TABLE XIV                                                       ______________________________________                                        Summary of Daily Food Consumption Data, in                                    Grams                                                                                      Study Week                                                       Group          -2      -1       1     2                                       ______________________________________                                        Males                                                                         Group 1 - saline control                                                      Mean           154.7   151.4    148.0 166.1                                   Standard deviation                                                                           23.61   39.23    27.62 5.37                                    N.sup.1        7       7        7     7                                       Group 2 - HPBCD                                                               Mean           170.0   166.9    161.1 171.9                                   Standard deviation                                                                           10.30   16.38    14.25 15.14                                   N.sup.1        7       7        7     7                                       Females                                                                       Group 1 - saline control                                                      Mean           136.1   158.4    141.0 169.0                                   Standard deviation                                                                           40.54   33.11    15.49 6.53                                    N.sup.1        7       7        7     7                                       Group 2 - HPBCD                                                               Mean           68.7    81.4     100.6 87.4                                    Standard deviation                                                                           23.70   20.66    14.48 31.78                                   N.sup.1        7       7        7     7                                       ______________________________________                                         .sup.1 N  number of days in the study week.                              

                                      TABLE XV                                    __________________________________________________________________________    Hematology Data                                                                          Males                 Females                                                 Pre-study control                                                                        Post study values                                                                        Pre-study control                                                                        Post study values                 Dose:      0 mg/kg                                                                            200 mg/kg                                                                           0 mg/kg                                                                            200 mg/kg                                                                           0 mg/kg                                                                            200 mg/kg                                                                           0 mg/kg                                                                             200 mg/kg                   __________________________________________________________________________    Blood component                                                               Red blood cell                                                                (× 10.sup.6 /mm.sup.3)                                                             5.48 7.00  5.50 6.83  6.61 5.68  6.31  5.27                        Hemoglobin (G/DL)                                                                        11.60                                                                              12.40 11.20                                                                              11.90 12.60                                                                              10.90 12.10 10.00                       Hematocrit (%)                                                                           39.90                                                                              42.90 39.10                                                                              40.20 42.20                                                                              37.60 39.90 33.40                       Mean corpuscle                                                                volume (FL)                                                                              73.00                                                                              61.00 70.00                                                                              59.00 64.00                                                                              66.00 63.00 63.00                       Mean corpuscle                                                                hemoglobin (pg)                                                                          21.20                                                                              17.70 20.10                                                                              17.40 19.10                                                                              19.20 19.20 19.00                       Mean corpuscle                                                                hemoglobin                                                                    concentrate (%)                                                                          29.10                                                                              28.90 28.60                                                                              29.60 29.90                                                                              29.00 30.30 29.90                       Platelet count                                                                (× 10.sup.3 /mm.sup.3)                                                             294.00                                                                             473.00                                                                              398.00                                                                             574.00                                                                              515.00                                                                             369.00                                                                              692.00                                                                              372.00                      Normal blood cells                                                            (/100 white blood                                                             cells)     0.00 0.00  0.00 0.00  0.00 0.00  0.00  0.00                        White blood cells                                                             (× 10.sup.3 mm.sup.3)                                                              14.50                                                                              11.30 13.30                                                                              9.50  7.70 6.90  5.50  3.70                        Segmented neutrophils                                                         (× 10.sup.3 /mm.sup.3)                                                             3.34 0.90  4.12 0.76  1.62 3.38  2.36  1.11                        Lymphocytes                                                                   (× 10.sup.3 /mm.sup.3)                                                             11.02                                                                              10.17 8.78 8.55  5.78 3.10  2.92  2.48                        Monocytes                                                                     (× 10.sup.3 /mm.sup.3)                                                             0.14 0.11  0.27 0.10  0.00 0.07  0.11  0.07                        Eosinophils                                                                   (× 10.sup.3 /mm.sup.3)                                                             0.00 0.11  0.13 0.10  0.31 0.34  0.11  0.04                        Basophils                                                                     (× 10.sup.3 /mm.sup.3)                                                             0.00 0.00  0.00 0.00  0.00 0.00  0.00  0.00                        Immature                                                                      neutrophils                                                                   (× 10.sup.3 mm.sup.3)                                                              0.00 0.00  0.00 0.00  0.00 0.00  0.00  0.00                        Prothrombin                                                                   time (sec.)                                                                              10.40                                                                              9.90  10.40                                                                              9.90  9.40 9.40  9.90  9.80                        Partial                                                                       thromboplastin                                                                time       24.90                                                                              24.40 23.90                                                                              23.40 22.30                                                                              23.40 9.80  25.40                       __________________________________________________________________________

                                      TABLE XVI                                   __________________________________________________________________________    Hematology Data                                                                          Males                 Females                                                 Pre-study control                                                                        Post study values                                                                        Pre-study control                                                                        Post study values                 Dose:      0 mg/kg                                                                            200 mg/kg                                                                           0 mg/kg                                                                            200 mg/kg                                                                           0 mg/kg                                                                            200 mg/kg                                                                           0 mg/kg                                                                             200 mg/kg                   __________________________________________________________________________    Blood component                                                               Glucose (mg/dL)                                                                          79.60                                                                              106.50                                                                              55.80                                                                              65.30 105.00                                                                             84.00 74.00 51.20                       Total proteins                                                                (G/dL)     8.00 8.80  7.10 8.00  8.20 8.40  7.80  8.10                        Albumin (G/dL)                                                                           4.20 4.90  4.00 4.30  4.60 4.40  4.40  4.10                        Globulin (G/dL)                                                                          3.90 3.90  3.10 3.70  3.50 4.00  3.30  4.00                        Albumin/Globulin                                                              (Ratio)    1.10 1.30  1.30 1.20  1.30 1.10  1.30  1.00                        Total bilirubin                                                               (mg/dL)    0.30 0.50  0.40 0.70  0.70 0.30  0.60  0.90                        Cholesterol                                                                   (mg/dL)    128.00                                                                             192.00                                                                              114.00                                                                             156.00                                                                              148.00                                                                             122.00                                                                              165.00                                                                              135.00                      Triglycerides                                                                 (mg/dL)    62.00                                                                              39.00 48.00                                                                              46.00 66.00                                                                              41.00 66.00 54.00                       Aspartate amino                                                               transferase                                                                   (IU/L)     40.00                                                                              44.00 45.00                                                                              33.00 51.00                                                                              35.00 42.00 26.00                       Alanine amino                                                                 transferase                                                                   (IU/L)     29.00                                                                              24.00 37.00                                                                              21.00 27.00                                                                              17.00 28.00 13.00                       Alkaline phosphate                                                            (IU/L)     431.00                                                                             588.00                                                                              549.00                                                                             560.00                                                                              381.00                                                                             279.00                                                                              345.00                                                                              270.00                      Blood urea                                                                    nitrogen (mg/dL)                                                                         30.90                                                                              25.80 40.60                                                                              20.80 29.30                                                                              21.00 20.80 20.00                       Creatinine                                                                    (mg/dL)    1.00 1.10  1.40 1.40  0.90 1.10  01.20 0.80                        Calcium (mg/dL)                                                                          11.40                                                                              12.10 9.30 9.80  10.90                                                                              10.00 9.70  9.30                        Ionic phosphate                                                               (mg/dL)    6.40 7.70  7.80 9.30  6.80 4.80  7.80  6.30                        Sodium (mmol/L)                                                                          148.00                                                                             148.00                                                                              145.00                                                                             148.00                                                                              147.00                                                                             143.00                                                                              149.00                                                                              149.00                      Potassium (mmol/L)                                                                       6.20 5.30  3.80 3.70  5.20 4.30  3.70  3.60                        Chlorine (mmol/L)                                                                        112.00                                                                             111.00                                                                              104.00                                                                             106.00                                                                              112.00                                                                             108.00                                                                              109.00                                                                              112.00                      __________________________________________________________________________

No changes in behavior were observed during the study. No weight changeswere observed (TABLE XIII) or changes in daily food consumption (TABLEXIV). No differences were seen in either the hematology values (TABLEXV) or the clinical chemistry values (TABLE XVI). No gross pathologicalchanges and no histopathological findings were observed. It is concludedthat in this study, HPBCD administered intravenously was devoid oftoxicological effects at a dose of 200 mg/kg.

The ultrafiltration, i.e., the ability of the dialysate to removefluids, was also studied. The results of this study are presented inTABLE XVII, below.

The procedure for this ultrafiltration study was similar to theprocedure utilized in obtaining the data for TABLE II, above, with theexceptions that the dwell time in the rats was 6 hours and theconcentration of glucose was 4.25% W/V and three concentrations of HPBCDwere used, that is 5, 10 and 15% W/V.

TABLE XVII shows that the 15% HPBCD dialysate actually removed bodyfluids from the rat. In contrast, the other dialysates are absorped bythe rat. This is an especially undesirable affect for the glucosecontaining dialysate as this results in unwanted caloric input aspreviously discussed.

                                      TABLE XVII                                  __________________________________________________________________________    Results of Ultrafiltration Study                                              (mean ± st. dev.)                                                                       Dialysate                                                                     Glucose                                                                              HPBCD                                                     __________________________________________________________________________    Concentration (% W/V)                                                                      4.25   5      10     15                                          Number of specimens                                                                        --     4      6      4                                           Osmolality.sup.1 (mOs)                                                                     480    290    340    --                                          Volume in                                                                     Per body weight (ml/100 g)                                                                 14.94 ± 0.12                                                                      14.96 ± 0.1                                                                       14.99 ± 0.10                                                                      14.92 ± 0.03                             Volume out                                                                    Per body weight (ml/100 g)                                                                 12.20 + 1.23                                                                         10.88 ± 1.12                                                                      12.43 ± 0.79                                                                      16.41 ± 0.94                             Difference.sup.2 (ml/100 g)                                                                -2.7 ± 1.4                                                                        -4.08 ± 1.0                                                                       -2.56 ± 0.8                                                                       +1.48 ± 0.48                             Percent change.sup.2                                                                       -18.0  -23.5  -16.7  +10.0                                       __________________________________________________________________________     .sup.1 Natural physical osmolality is in the range of about 290 to about      300.                                                                          .sup.2 A negative (-) value indicates a loss of dialysate to the body. A      positive (+) value indicates removal of body fluid from the body.        

This invention has been described in terms of specific embodiments setforth in detail, but it should be understood that these are by way ofillustration only and that the invention is not necessarily limitedthereto. Modifications and variations will be apparent from thisdisclosure and may be resorted to without departing from the spirit ofthis invention, as those skilled in the art will readily understand.Accordingly, such variations and modifications of the disclosed productsare considered to be within the purview and scope of this invention andthe following claims.

I claim:
 1. An aqueous composition suitable for peritoneal dialysis andcomprising:hydroxypropyl-beta-cyclodextrin in an amount in the range ofabout 5 to about 35 g/dl; sodium in an amount in the range of about 110to about 150 mEq/l; potassium in an amount in the range of about 0 toabout 5 mEq/l; calcium in an amount in the range of about 0 to about 6mEq/l; magnesium in an amount in the range of about 0 to about 4 mEq/l;and alkali equivalent in an amount in the range of about 35 to about 40mEq/l.
 2. The aqueous composition in accordance with claim 1 wherein thehydroxypropyl-beta-cyclodextrin has a degree of substitution of about 5to about 7 and is present in an amount in the range of about 7.5 toabout 25 g/dl.
 3. A method for peritoneal dialysis which comprises thesteps of:providing an aqueous dialysate containing:hydroxypropyl-beta-cyclodextrin in an amount in the range of about 5 toabout 35 g/dl; sodium in an amount in the range of about 110 to about150 mEq/l; potassium in an amount in the range of about 0 to about 5mEq/l; calcium in an amount in the range of about 0 to about 6 mEq/l;magnesium in an amount in the range of about 0 to about 4 mEq/l; andalkali equivalent in an amount in the range of about 35 to about 40mEq/l. introducing an aliquot of said dialysate into the peritonealcavity of a patient in need of dialysis; maintaining the introduceddialysate in the peritoneal cavity for a time period sufficient fortoxins present to enter the dialysate; and thereafter removing from theperitoneal cavity a dialysate aliquot having an increased toxin content.4. A substantially glucose-free dialysate composition suitable forperitoneal dialysis and comprising an aqueous dialysis solutioncontaining hydroxypropyl-beta-cyclodextrin having a degree ofsubstitution in the range of about 5 to about 7 and present in aconcentration of about 5 to about 35 g/dl.
 5. The aqueous dialysissolution in accordance with claim 4 whereinhydroxypropyl-beta-cyclodextrin having a degree of substitution of about5 to about 7 is present in a concentration of about 7.5 to about 25g/dl.
 6. A method for peritoneal dialysis which comprises the stepsof:providing an aqueous dialysate containing:hydroxypropyl-beta-cyclodextrin having a degree of substitution of about5 to about 7 in a concentration of about 5 to about 35 g/dl;introducting an aliquot of said dialysate into the peritoneal cavity ofthe patient in need of dialysis; maintaining the introduced dialysate inthe peritoneal cavity for a time period sufficient for toxins andadditional water to enter the dialysate; and thereafter removing fromthe peritoneal cavity a dialysate aliquot having an increased toxin andwater content.
 7. The method for peritoneal dialysis in accordance withclaim 6 wherein hydroxypropyl-beta-cyclodextrin is present in an aqueousdialysate in a concentration of about 7.5 to about 25 g/dl.